Ca Servik 3

The
n e w e ng l a n d j o u r na l
of
m e dic i n e
special article
Health and Economic Implications of HPV

Vaccination in the United States
Jane J. Kim, Ph.D., and Sue J. Goldie, M.D., M.P.H.
A bs t r ac t
Background
The cost-effectiveness of prophylactic vaccination against human papillomavirus types

16 (HPV-16) and 18 (HPV-18) is an important consideration for guidelines for immunization in the United States.
Methods
We synthesized epidemiologic and demographic data using models of HPV-16 and

HPV-18 transmission and cervical carcinogenesis to compare the health and economic outcomes of vaccinating preadolescent girls (at 12 years of age) and vaccinating older girls and women in catch-up programs (to 18, 21, or 26 years of age). We
examined the health benefits of averting other HPV-16related and HPV-18related
cancers, the prevention of HPV-6related and HPV-11related genital warts and juvenile-onset recurrent respiratory papillomatosis by means of the quadrivalent vaccine,
the duration of immunity, and future screening practices.
From the Department of Health Policy and

Management, Harvard School of Public
Health, Boston. Address reprint requests
to Dr. Kim at the Department of Health
Policy and Management, Program in
Health Decision Science, Harvard School
of Public Health, 718 Huntington Ave.,
2nd Fl., Boston, MA 02115, or at jkim@
hsph.harvard.edu.
N Engl J Med 2008;359:821-32.
Copyright 2008 Massachusetts Medical Society.
Results
On the assumption that the vaccine provided lifelong immunity, the cost-effectiveness ratio of vaccination of 12-year-old girls was $43,600 per quality-adjusted lifeyear (QALY) gained, as compared with the current screening practice. Under baseline
assumptions, the cost-effectiveness ratio for extending a temporary catch-up program for girls to 18 years of age was $97,300 per QALY; the cost of extending vaccination of girls and women to the age of 21 years was $120,400 per QALY, and the
cost for extension to the age of 26 years was $152,700 per QALY. The results were
sensitive to the duration of vaccine-induced immunity; if immunity waned after 10
years, the cost of vaccination of preadolescent girls exceeded $140,000 per QALY, and
catch-up strategies were less cost-effective than screening alone. The cost-effectiveness ratios for vaccination strategies were more favorable if the benefits of averting
other health conditions were included or if screening was delayed and performed at
less frequent intervals and with more sensitive tests; they were less favorable if vaccinated girls were preferentially screened more frequently in adulthood.
Conclusions
The cost-effectiveness of HPV vaccination will depend on the duration of vaccine immunity and will be optimized by achieving high coverage in preadolescent girls, targeting initial catch-up efforts to women up to 18 or 21 years of age, and revising
screening policies.
n engl j med 359;8 www.nejm.org august 21, 2008
The New England Journal of Medicine

Downloaded from nejm.org by epsilaainun bestari on January 11, 2016. For personal use only. No other uses without permission.
Copyright 2008 Massachusetts Medical Society. All rights reserved.
821
The
n the united states, cervical cancer

developed in an estimated 11,150 women and
caused death in 3600 women in 2007.1 Infection with high-risk oncogenic types of human
papillomavirus (HPV) is the cause of 100% of cervical cancers, 90% of anal cancers, 40% of vulvar
and vaginal cancers, at least 12% of oropharyngeal
cancers, and 3% of oral cancers.2 Worldwide, HPV
types 16 (HPV-16) and 18 (HPV-18) cause approximately 70% of cases of cervical cancer.3,4
Vaccines against HPV-16 and HPV-18 appear to
be highly efficacious in preventing HPV-16 and
HPV-18 infections and cervical lesions in girls and
women who have not previously been infected with
these types.5-9 The vaccine currently licensed in the
United States also prevents HPV types 6 and 11
(HPV-6 and HPV-11), which are responsible for
most genital warts and juvenile-onset recurrent
respiratory papillomatosis.10
There are important questions regarding the
appropriate target population for prophylactic vaccination against HPV-16 and HPV-18. Since the
vaccine is most efficacious before the onset of
sexual activity, most investigators agree that the
target population for routine immunization should
be adolescents who are approximately 12 years of
age.11,12 Recommended temporary catch-up programs to provide vaccine coverage to girls and
women 13 years of age and older range from an
upper age limit of 18 to 26 years.11,12
The impact of HPV vaccination on the rate of
cervical cancer will not be observable for decades;
thus, decisions regarding a vaccination policy will
inevitably rely on studies reporting intermediate
outcomes. Estimating the magnitude of the benefit of vaccination is further complicated when one
considers the extensive secondary-prevention program in the United States. This program, which
involves the use of cytology-based screening, is
recommended annually or biennially, starting
3 years after the first sexual intercourse and no
later than 21 years of age.13-15 HPV DNA testing is
recommended as a triage test for equivocal results
of cytologic analysis and in combination with
cytologic tests for primary screening in women
30 years of age or older.16
Before long-term data become available, mathematical models used in a decision-analytic framework that synthesize the best available data while
ensuring consistency with epidemiologic observations can project outcomes beyond those reported
in clinical trials, provide insight into key drivers
of cost-effectiveness, and be revised as new infor822
of
m e dic i n e
mation emerges. Extending previous studies of

HPV vaccination,17-22 we evaluated the cost-effectiveness of vaccinating 12-year-old girls and of
temporary catch-up programs. We considered the
dynamics of HPV transmission, the duration of
vaccine efficacy, the potential benefits of preventing noncervical HPV-related conditions, the anticipated changes in screening practice, and potential disparities in access to care.
Me thods
Analytic Overview
Synthesizing epidemiologic, clinical, and demographic data from the United States, we used empirically calibrated simulation models to estimate
the lifetime costs and benefits of vaccinating 12year-old girls (herein referred to as the vaccination
of preadolescent girls), as well as catch-up programs in girls and women up to 18, 21, or 26 years
of age, in the context of current cytology-based
screening in the United States. The base-case analysis was intended to be relevant to both the bivalent and quadrivalent HPV vaccines and therefore
focused on the outcomes of cervical cancer. To examine the additional benefits of the vaccine for
which empirical data were available, we also assessed the effect of the quadrivalent vaccine on
HPV-6associated and HPV-11associated genital
warts. Although the efficacy of the vaccine against
noncervical HPV-16associated and HPV-18associated cancers and HPV-6associated and HPV11associated juvenile-onset recurrent respiratory
papillomatosis is more uncertain, we assessed the
effect of their inclusion on our results. Although
we assumed lifelong complete protection against
the vaccine-targeted types of HPV in the base-case
analysis, we evaluated the effect of waning vaccineinduced immunity (without and with a booster).
Other uncertainties that we evaluated included
cross-protection of the vaccine against high-risk
types of HPV that did not include HPV-16 and
HPV-18, the increased incidence of high-risk types
of HPV that did not include HPV-16 and HPV-18,
disparities in vaccination and screening coverage,
and revisions in screening practices.
We adopted a societal perspective, discounted
costs and benefits by 3% annually, and expressed
benefits as quality-adjusted life-years (QALYs)
gained. After eliminating strategies that were more
costly and less effective or less costly and less costeffective than an alternative strategy, incremental cost-effectiveness ratios were calculated as the

Cost-Effectiveness of HPV Vaccination
additional cost divided by the additional health

benefit associated with one strategy as compared
with the next-less-costly strategy. Although there
is no consensus on a cutoff point for good value
for resources, we interpreted our results in terms
of a commonly cited threshold of $50,000 per
QALY gained, as well as an upper-bound threshold
of $100,000 per QALY gained.23
Models
We used a flexible modeling approach that included a dynamic model to simulate the sexual transmission of HPV-16 and HPV-18 infections between
men and women and an individual-based stochastic model to simulate the cervical carcinogenesis
associated with all types of HPV. Both models have
been described previously.24,25 Briefly, the dynamic
model is an open-cohort, age-structured compartmental model in which women and men form sexual partnerships over time. Women and men enter
the susceptible pool on sexual initiation starting
at 10 years of age, and with each partnership,
HPV-16 or HPV-18 may be transmitted, depending
on the number of new partners, the prevalence of
HPV among the opposite sex, and the probabilities of transmission of HPV-16 and HPV-18 from
an infected partner. After the first HPV infection
and clearance, partial type-specific natural immunity develops, effectively reducing a persons susceptibility to future infections of the same type.
Grade 1 cervical intraepithelial neoplasia (CIN 1)
or grade 2 or 3 CIN (CIN 2/3) can develop in women with HPV-16 or HPV-18 infection, and invasive
cancer may develop in women with CIN 2/3.
The individual-based stochastic model has a
similar structure. However, all types of HPV (categorized as HPV-16, HPV-18, other high-risk types
of HPV, and low-risk types of HPV) are included,
the incidence of HPV is a function of age and individual-level characteristics, it keeps track of each
persons history (e.g., vaccination, screening, treatment, and past abnormalities), and it can accommodate complex screening strategies.25,26 The dynamic model was used to estimate reductions in
the age-specific incidence of HPV-16 and HPV-18
with vaccination, reflecting the direct benefits to
persons who were vaccinated, as well as indirect
benefits, because of herd immunity, to those who
were not vaccinated. The generated reductions in
the incidence of HPV-16 and HPV-18 served as
inputs to the stochastic model, which was used to
compare multiple strategies for the prevention of
cervical cancer. The specific features of the individ-
ual-based stochastic model allowed us to identify

the synergies between vaccination and screening,
study the implications of disparities in vaccination
and screening coverage, assess the effect of crossprotection to other types of HPV, and explore the
potential for an increase in the incidence of types
of HPV that were not targeted by the vaccine.
The initial variables from the models were
based on data from epidemiologic studies, cancer
registries, and demographic statistics. The models
were calibrated with the use of a likelihood-based
approach to fit to empirical data, such as the agespecific prevalence of HPV, the age-specific incidence of cervical cancer, and the distribution of
types of HPV observed among girls and women
in the U.S. population.3,4,27-31 These approaches
have been described elsewhere,24,25 and details
relevant to the current analysis are provided in the
Supplementary Appendix, available with the full
text of this article at www.nejm.org.
For noncervical cancer conditions, data included the incidence of other HPV-16associated and
HPV-18associated cancers; the incidence of lowrisk, HPV-associated genital warts and juvenileonset recurrent respiratory papillomatosis; the
proportion of each disease attributable to vaccinetargeted types of HPV; and the disease-specific
quality of life, costs, and mortality2,10,32-41 (Table 1). Costs (in 2006 U.S. dollars) included the
direct medical costs associated with screening,
diagnosis, and treatment (e.g., tests, procedures,
and hospitalizations) and with vaccination (e.g.,
three doses of the vaccine at $120 per dose, wastage, supplies, and administration).42-45 Direct nonmedical costs such as the patients time and transportation were included for all strategies.
Cost-Effectiveness Analysis
To estimate the long-term outcomes associated

with vaccination and screening, we projected the
lifetime health and economic consequences for
all birth cohorts of women in the first 10 years of
the vaccine program. We included all birth cohorts,
regardless of whether or not they received the vaccine, to capture the benefits of herd immunity in
unvaccinated persons (see the Supplementary Appendix). The incremental costs and the health benefits of each vaccination strategy as compared with
screening alone served as the basis for calculations
of cost-effectiveness.
Strategies included HPV vaccination of 12-yearold girls and catch-up vaccination over a 5-year
period for girls and women from 13 years of age

823
The
of
m e dic i n e
Table 1. Values for HPV-Related Health Conditions in the Model.*

Variable
Values
Reference
Cervical cancer
Incidence (no./100,000 women)
4.262.8
Five-year survival (%)
16.592.0
National Cancer Institute32
Quality-of-life adjustment
0.480.76
Myers et al.,36 Gold et al.39
Cases attributable to HPV-16 and HPV-18 (%)

Cost per case ($)
70.0
26,54045,540
Parkin and Bray2

Goldie et al.33
Vulvar cancer
0.224.9
77.8
0.68

Cost per case ($)
32.0
20,430

Gold et al.39
Parkin and Bray2
Hu and Goldie38
Vaginal cancer
0.16.0
55.7

0.68

Cost per case ($)
32.0
23,440
Gold et al.39
Parkin and Bray2
Hu and Goldie38
Anal cancer
0.05.6
66.2

0.68

Cost per case ($)
82.8
31,300
Gold et al.39
Parkin and Bray2
Hu and Goldie38
Oral cancer
0.213.9
62.6
0.68
2.9
Cost per case ($)
37,370

Parkin and Bray2
Hu and Goldie38
Oropharyngeal cancer
0.01.1
62.6

0.68

Cost per case ($)
10.7
37,370
to 18, 21, or 26 years of age. On the basis of rates

of vaccinations among adolescents in the United
States,46 we assumed that approximately 75% of
the target population was covered within the first
5 years after the beginning of the program, at a
coverage rate of 25% per year (Fig. 1). The efficacy of the vaccine was assumed to be lifelong and
824
Parkin and Bray2

Hu and Goldie38
100% against the types of HPV targeted by the

vaccine among girls and women without a previous history of those infections.
All strategies included routine screening for
cervical cancer with conventional or liquid-based
cytologic testing, beginning in women at an average age of 20 years, according to U.S. guide-

Table 1. (Continued.)
Variable
Values
Reference
Genital warts
Prevalence (no./1000 women)
0.076.20
0.91
Insinga et al.35
Insinga et al.,35 Myers et al.36
100
Lacey et al.10
Cost per case ($)
430
Hu and Goldie38
Juvenile-onset recurrent respiratory papillomatosis

Incidence (no./100,000 children 014 yr old)
4.30
Derkay37
0.69
Bishai et al.40

Cost per case ($)
Lacey et al.10
100
Hu and Goldie38
62,010
* Ranges represent age-specific values, and rates are annual rates unless otherwise noted. HPV denotes human papillomavirus.
Incidence rates for cervical cancer were generated by the calibrated stochastic model in the absence of screening or vaccination (i.e., natural
history).
The 5-year survival for cervical cancer varied according to the stage (i.e., 92.0% for local, 55.7% for regional, and 16.5% for distant disease).
The quality-of-life adjustment assumed a health-state utility weight of 0 (death) to 1 (perfect health). The health-state utility weight for cervical cancer varied according to the stage: 0.76 for local cancer, 0.67 for regional cancer for a period of 5 years, and 0.48 for distant cancer
over the lifetime with disease. For noncervical cancers, we assumed an average health-state utility weight of 0.68 over the lifetime with disease in order to reflect a weighted average of stage-specific utility weights and distribution of disease according to stage. For genital warts,
we assumed a health-state utility weight of 0.91 over 3 months. All disease-specific utility weights were multiplied to baseline age-specific
utility weights in order to estimate the overall utility weight (data are from Fryback et al.41).
The cost per case is expressed in 2006 U.S. dollars and represents the average discounted lifetime costs of a new case of disease, including
direct medical costs (i.e., the cost of procedures, hospitalizations, and office visits). The costs of treatment of cervical cancer varied according to stage (e.g., $26,540 for local, $28,430 for regional, and $45,540 for distant disease) and included direct nonmedical costs such as the
patients time and transportation.
lines that recommend that screening should start

3 years after the first sexual intercourse.13,47 Abnormal results of cytologic tests were managed
according to standard clinical guidelines.48 On
the basis of reported patterns of cervical-cancer
screening in women in the United States,49-51 we
assumed that 53% of women were screened annually, 17% every 2 years, 11% every 3 years, and
14% every 5 years and that 5% were never screened.
We considered scenarios in which girls who were
unlikely to be vaccinated were also unlikely to be
screened. We also assessed the implications of
screening less frequently (every 3 or 5 years), delaying the initiation of screening (until 25 years
of age), and the use of HPV DNA testing.52
To gauge the benefits of the quadrivalent vaccine against HPV-6 and HPV-11 in women, we
modeled the age-specific incidence and duration
of genital warts,35 including their effect on quality of life and treatment costs,36,38 and we estimated the quality-adjusted life expectancy gained
and costs averted with vaccination. Similarly, we
estimated the number of cases of juvenile-onset
recurrent respiratory papillomatosis averted per
vaccinated woman using data on the number of
births per woman,53 annual incidence rates of juvenile-onset recurrent respiratory papillomatosis
per live child,37 costs per case, and effects on
quality of life.38,40 For both vaccines, we modeled
age-specific incidence rates of HPV-16associated and HPV-18associated noncervical cancer
among women,32 taking into account cancer-specific mortality and health-state utility weights (i.e.,
values from 0 to 1 indicating the quality of a persons state of health, with 0 indicating death and
1 indicating perfect health),32,39 to estimate quality-adjusted life expectancy gained and costs averted (Table 1). Vaccination was assumed to reduce
the proportion of cases attributable to vaccinetargeted types of HPV, and we varied the efficacy
on these conditions from 50% to 100% (see the
Supplementary Appendix for additional details on
noncervical conditions).
R e sult s
Cost-Effectiveness of Vaccination
The routine vaccination of 12-year-old girls, in the

context of current screening and assuming lifelong vaccine-induced immunity, had an incremen-

825
The
Program
Age (yr)
12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
Year 1
Year 2
Year 3
Year 4
Year 5
Year 6
Year 7
Year 8
Year 9
Year 10
76%
of
m e dic i n e
Inclusion of protection against HPV-6related

and HPV-11related genital warts reduced the cost
per QALY for vaccination of preadolescent girls by
20% to $34,900, for catch-up to 18 years of age by
17% to $81,000, and for catch-up to 21 years of age
by 16% to $101,300. The cost per QALY for catchup to 26 years of age was reduced by only 13%,
to $133,600.
Inclusion of Other HPV-Associated
Conditions
= Vaccination of 12-yr-old girls only (no catch-up);

coverage 25%/yr
+
= Vaccination of 12-yr-old girls+catch-up to age 18 yr;

coverage 25%/yr

coverage 25%/yr

coverage 25%/yr
= Vaccination of 12-yr-old girls only; coverage 75%/yr

= Vaccination of girls who are 13 yr old at yr 1 of vaccination;
coverage 25%/yr
Figure 1. Vaccination Coverage.

1st
RETAKE
AUTHOR: Kim
ICM
Pink boxes indicate
vaccination
of preadolescent 12-year-old girls at a cov2nd
1
of
2
FIGURE:
REG
F
erage rate of 25% per year for the first 5 years of the vaccination
3rd program;
CASE
purple boxes indicate
a coverage rate of 75% in years 6Revised
to 10 of the vaccinaLine each
4-Cbirth cohort
tion program.EMail
Without a catch-up program,
SIZE of 12-yearARTIST: ts
H/T
H/T
olds had no future
single year. YelEnon opportunities for vaccination beyond a22p3
Combo
low, light-orange, and dark-orange boxes indicate catch-up vaccination of
AUTHOR, PLEASE NOTE:
girls and women from
age 13
up to 18, 21, or 26 years of age, which ocFigure has been redrawn and type has been reset.
curred over a 5-year period atPlease
25% coverage
per year. Therefore, an addicheck carefully.
tional 25% of the initial cohort of 12-year-old girls who were not vaccinated
in the first year
another opportunity to receiveISSUE:
the vaccine
in the sec35908
08-21-08
JOB: had
ond year of the program, when they were 13 years old; such opportunities
continued through program year 5. Brown boxes show catch-up vaccination
in the initial cohort of 13-year-old girls. In year 1 of the vaccination program, 25% of the 13-year-old girls were assumed to be covered; in year 2,
among the 75% of 13-year-olds who were not vaccinated in year 1, 25%
would be covered when they were 14 years old. At the end of year 5, 76% of
the original cohort of 13-year-olds was covered. The number of opportunities for vaccination depended on the specific catch-up strategy; for example, a 16-year-old in the first year of the program would have only three
chances of receiving the vaccine in a catch-up program up to 18 years of
age, since she would be older than 18 years of age in program year 4.
When the potential benefits associated with

preventing noncervical HPV-16related and HPV18related cancers and HPV-6related and HPV-11
related juvenile-onset recurrent respiratory papillomatosis were included, cost-effectiveness ratios
were reduced. The magnitude of these reductions
depended on the specific outcomes that were included and on assumptions about the efficacy of
the vaccine (Fig. 2). In all scenarios, the cost of
vaccination of preadolescent girls remained below $50,000 per QALY, and catch-up vaccination
of girls to 18 years of age remained between
$50,000 and $100,000 per QALY.
Effect of Waning Immunity, Vaccine
Cross-Protection, and Type Replacement
If vaccine-induced immunity lasted only 10 years,

the vaccination of preadolescent girls provided only
2% marginal improvement in the reduction in the
risk of cervical cancer as compared with screening alone, and it cost $144,100 per QALY, whereas
catch-up programs were more costly and less effective than screening alone (Table 3). With a completely efficacious vaccine booster at 10 years, the
cost of vaccination of preadolescent girls was
$83,300 per QALY, although catch-up strategies exceeded $125,000 per QALY. There were marginal
improvements in cost-effectiveness when crossprotective effects were included against other highrisk types of HPV.8 Furthermore, in a separate
analysis, with a 5% increase in the baseline risk of
infection with high-risk types of HPV other than
tal cost-effectiveness ratio of $43,600 per QALY HPV-16 and HPV-18, the cost per QALY of vaccigained, as compared with screening alone (Table nation of preadolescent girls increased from
2). The addition of a 5-year catch-up program for $43,600 to $53,000.
girls between the ages of 13 and 18 years cost
$97,300 per QALY, and extension to 21 years of age Effect of Patterns of Vaccination
cost $120,400 per QALY. The extension of the catch- and Screening Coverage
up program to 26 years of age cost $152,700 per If 5% of women in the United States were neither
QALY, as compared with the catch-up program to screened nor vaccinated, all strategies that involved
21 years of age.
a catch-up program exceeded $100,000 per QALY;
826

Table 2. Cost-Effectiveness of Vaccination of Preadolescent Girls and Temporary Catch-Up Programs.*
Strategy
Base Case
With Outcomes Related

to HPV-6 and HPV-11
Genital Warts
$/QALY
Screening only
Vaccination (age 12 yr)
43,600
34,900
Vaccination (age 12 yr) plus catch-up vaccination (age 1318 yr)
97,300
81,000
120,400
101,300
152,700
133,600
* The values represent incremental cost-effectiveness ratios (i.e., the additional cost divided by the additional health benefit compared with the next-less-costly strategy) expressed as cost per quality-adjusted life-year ($/QALY). All costs are
expressed in 2006 U.S. dollars. HPV denotes human papillomavirus.
All strategies included current cytologic screening (see the Methods section).
The base-case analysis reflected the outcomes related to cervical cancer only.
The analysis included outcomes related to cervical cancer and HPV-6associated and HPV-11associated genital warts
in girls and women.
Since screening only is the baseline strategy, it is not associated with an incremental cost-effectiveness ratio.
catch-up to 26 years of age exceeded $200,000

per QALY (Table 4). The ratios became even less
attractive when we assumed that girls who were
vaccinated were preferentially screened more frequently in adulthood.
Even if all women were equally likely to be
screened, the cost-effectiveness of vaccination was
influenced by the frequency of screening and test
protocols. With annual and biennial screening, the
cost of vaccination of preadolescent girls increased
to $118,200 and $45,800 per QALY, respectively;
the negative effect on the cost-effectiveness of
catch-up programs was greater, with catch-up vaccination of girls and women up to 26 years of age
increasing to more than $300,000 and approximately $190,000 per QALY, respectively. The costeffectiveness ratio for the vaccination of preadolescent girls associated with initiating screening
later (e.g., at 25 years of age) with the use of cytologic tests with HPV triage every 3 years, followed by combined HPV DNA testing and cytologic tests for primary screening after 35 years of
age, was similar to the base case, although catchup vaccination programs for women up to 21 and
26 years of age were associated with higher costeffectiveness ratios (see additional results in the
Supplementary Appendix).
QALY) if high coverage can be achieved in the primary target group of 12-year-old girls and if vaccine-induced immunity is lifelong. Under these
conditions, if we are willing to pay $100,000 per
QALY, a catch-up program for girls between 13
and 18 years of age appears to be reasonable, especially when we include the benefits of averting
genital warts (with the use of the quadrivalent vaccine) or the benefits of cross-protection against
other high-risk types of HPV not including HPV16 and HPV-18 (as reported with the bivalent vaccine). Extending the catch-up program to 21 years
of age is less cost-effective, but it also becomes
more favorable when the potential benefits of preventing noncervical HPV-16associated and HPV18associated cancers in women are included.
Extending vaccine coverage to women up to 26
years of age generally exceeds $130,000 per QALY.
This result is not unexpected, since nearly 90% of
women in the United States have had vaginal intercourse by 24 years of age47 and up to 30% of
women may be exposed to HPV in the first year
of intercourse.54 The cost of extending a catch-up
program to women up to 26 years of age is less
than $100,000 per QALY only in the context of
100% lifelong efficacy against other outcomes associated with HPV-16, HPV-18, HPV-6, and HPV-11
in women; these outcomes include cervical cancer,
warts, other cancers, and juvenile-onset recurrent
Discussion
respiratory papillomatosis. The cost of extending
Vaccination against HPV-16 and HPV-18 is expected this program is more than $200,000 per QALY
to be economically attractive (i.e., <$50,000 per when a booster is required to maintain lifelong

827
The
160,000
Incremental Cost-Effectiveness of Vaccination

($/QALY)
140,000
120,000
of
m e dic i n e
Cervical cancer only

Cervical cancer+genital warts
Cervical cancer+JORRP (50% efficacy)
Cervical cancer+JORRP (100% efficacy)
Cervical cancer+other cancers (50% efficacy)
Cervical cancer+other cancers (100% efficacy)
All outcomes (50% efficacy)
All outcomes (100% efficacy)
100,000
80,000
60,000
40,000
20,000
12
1218
1221
1226
Age Group (yr)
Figure 2. Effect of Inclusion of Other Health Conditions on the Cost-Effectiveness of Vaccination Strategies.
1st
RETAKE
AUTHOR:
Kim of the vaccine against
The solid lines represent analyses ICM
in which
the efficacy
human
papillomavirus (HPV) was as2nd
FIGURE:
2
of
2
REG
F
sumed to be 100% among girls and
women
without a previous history of type-specific
infection (for all conditions).
3rd
The dashed lines represent analyses
in which the efficacy of the vaccine was
assumed to be 50% (only for cancers
CASE
Revised
Line
4-C
other than cervical cancer and juvenile-onset
recurrent respiratory
papillomatosis
EMail
SIZE [JORRP]; the efficacy remained
ARTIST: ts
H/T
H/T
100% for cervical cancer and genital
warts)
among
girls
and
women
without a22p3
previous history of type-specific inEnon
Combo
fection. In all analyses, the efficacy of the vaccine was assumed to be 0% among persons with a previous type-speAUTHOR,
PLEASE
NOTE:
cific infection or infections. Including the potential
benefits
of the
vaccine against noncervical HPV-16related and
Figure has been redrawn and type has been reset.
HPV-18related cancers, HPV-6related and HPV-11related
JORRP, or both reduced the cost-effectiveness ratios,
Please check carefully.
but the magnitude of the reduction depended on the specific outcomes included and the assumptions about efficacy. For instance, including otherJOB:
cancers
ratios08-21-08
from 18% to 30% depending on the
35908reduced the cost-effectivenessISSUE:
efficacy of the vaccine, whereas including JORRP had less of an effect. Under all assumptions, the cost of vaccination of preadolescent girls (i.e., 12-year-old girls) remained below $50,000 per quality-adjusted life-year (QALY), and
the cost of catch-up vaccination of girls to 18 years of age was between $50,000 and $100,000 per QALY. The cost of
catch-up vaccination of girls and women to 21 years of age decreased below $100,000 per QALY when other cancers
or all outcomes were included, and the cost of catch-up vaccination to 26 years of age exceeded $100,000 per QALY,
unless all outcomes were included with a vaccine efficacy of 100% for all conditions.
immunity, when there are disparities in screening

and vaccination coverage, and when vaccinated
girls undergo frequent screening in adulthood. The
benefits of vaccine in most HPV-16 and HPV-18
noncervical cancers and HPV-6 and HPV-11 juvenile-onset recurrent respiratory papillomatosis have
not been shown in clinical studies.
Our results were sensitive to the duration of
vaccine-induced immunity; if immunity lasted 10
years, the vaccination of preadolescent girls ex-
828
ceeded $140,000 per QALY, and all catch-up strategies were less cost-effective than screening alone.
Although immunologic data have provided support
for a strong initial immune response with antibody levels persisting at a level higher than the
level after natural infection,9,55,56 observations in
published reports are limited to 5 years after vaccination. With partial natural immunity to typespecific infection, if a vaccinated girl loses vaccineinduced protection and becomes susceptible at a

Table 3. Effect of Uncertain Vaccine Properties on Cost-Effectiveness.*
Strategy
Base Case
Waning Immunity
at 10 Yr
Booster
at 10 Yr
Inclusion of CrossProtection against Other

High-Risk Types of HPV
$/QALY
Screening only**
43,600
144,100
83,300
33,700
Vaccination (age 12 yr) plus catchup vaccination (age 1318 yr)
97,300
Not cost-effective
140,700
79,300
120,400
Not cost-effective
185,400
102,200
152,700
Not cost-effective
233,500
129,500
* The values represent incremental cost-effectiveness ratios (i.e., the additional cost divided by the additional health
benefit compared with the next-less-costly strategy) expressed as cost per quality-adjusted life-year ($/QALY). A strategy that is not cost-effective is more costly and less effective than another strategy. All costs are expressed in 2006
U.S. dollars. HPV denotes human papillomavirus.
All strategies included current cytologic screening (see the Methods section).
The base-case analysis reflected the outcomes related to cervical cancer only.
The analysis assumed full vaccine-induced protection up to 10 years, after which protection waned completely.
The analysis assumed a vaccine booster was administered to all previously vaccinated persons 10 years after initial
vaccination and provided lifelong protection. The booster was assumed to cost $250 per vaccinated person (including
the cost of the vaccine dose, supplies, wastage, administration, and patients time and transportation, as well as an
additional cost for the booster campaign and outreach efforts).
The efficacy of the vaccine against other high-risk types of HPV (i.e., other than HPV-16 and HPV-18) was assumed to
be 27.1%; data are from Paavonen et al.8
** Since screening only is the baseline strategy, it is not associated with an incremental cost-effectiveness ratio.
later age when the risk of cancer may be higher,

an increased risk of cervical cancer is plausible.
There are no empirical data to show whether reinfection or reactivation of a previous infection
predominates in older women; as previously de
scribed,17 which one of these predominates will
influence the implications of waning vaccine protection. There are other important uncertainties.
Although HPV infections may be independent
from one another,56 our exploratory analysis showed
that replacement of the vaccine-targeted types of
HPV with other high-risk types could be influential. Vaccination against HPV may also alter sexual behavior in the population or lead to a misperception that screening is no longer necessary.
These uncertainties highlight the priorities for
surveillance of epidemiologic characteristics and
behaviors after vaccination against HPV.
Our results of vaccinating preadolescent girls
were consistent with those of other studies.17-22,57,58
Elbasha et al.21 reported that the cost of a catchup program in women up to 24 years of age was
less than $5,000 per QALY; none of our strategies
had a cost-effectiveness ratio this low, and the cost

of a catch-up program in women up to 26 years of
age generally exceeded $100,000 per QALY. Differences in assumptions have been summarized in
several review articles.59-61 Our findings, which
were consistent with those of others,20,22 were that
high vaccination coverage warranted modification
of screening protocols and that the cost-effectiveness of vaccination was enhanced with less frequent screening with more sensitive tests and beginning at later ages.
Our analysis has important limitations. Data
on sexual behavior were primarily based on population averages from large surveys, and there were
limited data on type-specific HPV transmission
according to age and sex. By means of a modelfitting process, we estimated probabilities of transmission that were higher than those of some other
analyses62,63; as better data become available, the
estimation of these variables may be refined.
Other limitations of the data included the incidence, mortality, and quality of life associated with
noncervical HPV-related cancers, the long-term ef-

829
The
of
m e dic i n e
Table 4. Effect of Disparities in Vaccination and Screening Coverage and Revised Cervical-Cancer Screening Policies on Cost-Effectiveness.*
Strategy
Base Case
Vaccine Coverage
Screening Policy
Only Women
Who Will Be
Screened
Only Women
Who Will Be
Screened
Frequently
Cytologic
Screening
(1 yr)
Cytologic
Screening
(2 yr)
Revised
Screening
(3 yr)
$/QALY
Screening only**
43,600
47,900
106,000
118,200
45,800
40,900
Vaccination (age 12 yr) plus catchup vaccination (1318 yr)
97,300
121,900
136,300
186,700
102,400
103,500
120,400
153,300
172,400
250,600
120,600
128,700
152,700
204,700
231,000
324,200
189,700
185,400
* The values represent incremental cost-effectiveness ratios (i.e., the additional cost divided by the additional health benefit compared with
the next-less-costly strategy), expressed as the cost per quality-adjusted life-year ($/QALY). All analyses reflect outcomes related to cervical
cancer only. All costs are expressed in 2006 U.S. dollars. HPV denotes human papillomavirus.
The base-case analysis included current cytologic screening (see the Methods section).
The analysis assumed that women who were never screened were also not vaccinated.
The analysis assumed that women who were screened less frequently (i.e., every 5 years or never) were also not vaccinated.
The analysis assumed the base-case screening test and age for initiation of screening, but the screening interval was changed to every
1 or 2 years, which is consistent with current screening guidelines.
The analysis assumed cytologic screening with HPV DNA testing as triage for equivocal results starting at 25 years of age, with a switch to
combined cytologic and HPV DNA testing starting at 35 years of age.
** Since screening only is the baseline strategy, it is not associated with an incremental cost-effectiveness ratio.
ficacy of the vaccine against cervical lesions and

warts, and the efficacy of the vaccine against noncervical cancers. As with all model-based analyses,
there are trade-offs with regard to the choice of
model structure; we used two different modeling
techniques to try to best capture the features of
HPV infection and cervical carcinogenesis that
were most relevant to the key policy questions. The
complexities that are introduced with the use of
multiple models should be explored further.24
A decision-analytic approach allows for acknowledgment of uncertainty while informing
decisions that need to be made now. Accordingly,
we emphasized broad qualitative themes that we
found to be consistent throughout a range of assumptions. The cost-effectiveness of HPV vaccination in the United States will likely be optimized
by achieving universal coverage in young adoles-
cent girls and targeting initial catch-up efforts to

girls and women younger than 21 years of age.
Optimal synergies between vaccination and screening will involve revisions to current screening
practice. Priorities for empirical data collection
include surveillance to understand the HPV typespecific epidemiologic factors and screening behavior in vaccinated populations, the duration of
vaccine-induced protection, and the long-term impact on other HPV-related conditions.
Supported by grants from the National Cancer Institute (R01
CA93435), the Centers for Disease Control and Prevention, and
the American Cancer Society, and by the Bill and Melinda Gates
Foundation (30505) for related work in developing countries.
No potential conflict of interest relevant to this article was
reported.
We thank the entire cervical-cancer prevention team at the
Program in Health Decision Science, Harvard School of Public
Health, including Jeremy Goldhaber-Fiebert, Jesse Ortendahl,
Meredith OShea, Katie Kobus, Steven Sweet, Nicole Gastineau
Campos, and Bethany Andres-Beck, for their contributions.
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The

Health and Economic Implications of HPV

The cost-effectiveness of prophylactic vaccination against human papillomavirus types

We synthesized epidemiologic and demographic data using models of HPV-16 and

From the Department of Health Policy and

n engl j med 359;8 www.nejm.org august 21, 2008

The New England Journal of Medicine

n the united states, cervical cancer

mation emerges. Extending previous studies of

n engl j med 359;8 www.nejm.org august 21, 2008

The New England Journal of Medicine

Cost-Effectiveness of HPV Vaccination

additional cost divided by the additional health

ual-based stochastic model allowed us to identify

To estimate the long-term outcomes associated

n engl j med 359;8 www.nejm.org august 21, 2008

The New England Journal of Medicine

Table 1. Values for HPV-Related Health Conditions in the Model.*

Five-year survival (%)

National Cancer Institute32

Myers et al.,36 Gold et al.39

Cases attributable to HPV-16 and HPV-18 (%)

Parkin and Bray2

Five-year survival (%)

Cases attributable to HPV-16 and HPV-18 (%)

National Cancer Institute32

National Cancer Institute32

National Cancer Institute32

Five-year survival (%)

Cases attributable to HPV-16 and HPV-18 (%)

National Cancer Institute32

National Cancer Institute32

Five-year survival (%)

Cases attributable to HPV-16 and HPV-18 (%)

Five-year survival (%)

Cases attributable to HPV-16 and HPV-18 (%)

Cost per case ($)

National Cancer Institute32

National Cancer Institute32

National Cancer Institute32

Five-year survival (%)

Cases attributable to HPV-16 and HPV-18 (%)

to 18, 21, or 26 years of age. On the basis of rates

Parkin and Bray2

100% against the types of HPV targeted by the

n engl j med 359;8 www.nejm.org august 21, 2008

The New England Journal of Medicine

Cost-Effectiveness of HPV Vaccination

Cases attributable to HPV-6 and HPV-11 (%)

Cost per case ($)

Juvenile-onset recurrent respiratory papillomatosis

Cases attributable to HPV-6 and HPV-11 (%)

lines that recommend that screening should start

The routine vaccination of 12-year-old girls, in the

n engl j med 359;8 www.nejm.org august 21, 2008

The New England Journal of Medicine

Inclusion of protection against HPV-6related

= Vaccination of 12-yr-old girls only (no catch-up);